POS1111 TREATMENT WITH UPADACITINIB RESULTS IN THE INHIBITION OF A BROAD RANGE OF POTENTIALLY PATHOGENIC PATHWAYS IN NR-AXSPA AND BDMARD-IR AS PATIENTS: PROTEOMIC ANALYSIS FROM THE SELECT-AXIS 2 PHASE 3 STUDIES
Authors: T. Sornasse, I. H. Song, P. Wung, Y. Bi, B. Ravishankar, H. A. Hu, W. P. Maksymowych
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Upadacitinib (UPA) 15 mg QD, an oral Janus kinase inhibitor, demonstrated efficacy in patients with non-radiographic axial spondyloarthritis (nr-axSpA) and patients with ankylosing spondylitis (AS) with an inadequate response (IR) to biological disease-modifying antirheumatic drugs (bDMARD) in SELECT-AXIS 2<sup>[1,2]</sup> (NCT04169373). <h3>Objectives</h3> To identify biological pathways modulated by UPA in nr-axSpA and bDMARD-IR AS patients based on an extensive proteomic profiling, emphasizing those associated with disease activity at baseline. <h3>Methods</h3> A subgroup of patients from the SELECT-AXIS 2 program, with available biomarker samples, were selected for analysis (nr-axSpA PBO: n = 82; nr-axSpA UPA: n = 82; bDMARD-IR AS PBO: n = 111; bDMARD-IR AS UPA: n = 112). In addition, samples from 24 age- and gender-matched healthy volunteers (HVs) were included in the analysis. The levels of 1463 unique protein biomarkers (pBMs) were analyzed using proximity extension assay technology. Differences in pBMs levels between patients and HVs and their changes from baseline upon treatment were expressed as Log2 Fold Changes (Log2 FC). Relationships between pBMs levels and the Ankylosing Spondylitis Disease Activity Score using C-reactive protein (ASDAS-CRP) were derived using Pearson's correlation. A repeated measure mixed linear model identified pBMs differentially modulated by UPA. All tests were corrected for multiple testing using the Benjamini-Hochberg method. Significance threshold was defined as FDR ≤ 0.05. We used a commercially available software application for pathway analysis. <h3>Results</h3> At baseline, we identified 174 (nr-axSpA) and 178 (bDMARD-IR AS) pBMs that were significantly differentially expressed in patients compared to HVs. Only 24 out of 1463 pBMs tested were differentially expressed between the two patient populations. Notably, interleukin-6, matrix metalloproteinase-1, metalloproteinase-3, and interleukin 17 receptor A were significantly more elevated in bDMARD-IR AS patients than in nr-axSpA patients. The pathway enrichment analysis on the differential pBMs pointed to a dysregulation of the adaptive and innate immune systems, increase in endothelial activation, and damage to connective tissue in both patient groups, although more pronounced in bDMARD-IR AS patients. Baseline levels of 49 (4 negatives and 45 positives) and 178 (130 negatives and 48 positives) pBMs correlated with baseline ASDAS-CRP in the nr-axSpA and bDMARD-IR AS patients, respectively. Treatment with UPA resulted in a broad modulation of pBMs at weeks 2 and 14 in both patient groups, with a larger effect in bDMARD-IR AS patients than in nr-axSpA patients. Based on pathway prediction analysis, the effects of UPA on pBMs were consistent with the inhibition of the adaptive (T cell activation and migration, and antigen presenting cell activation) and innate (phagocyte and granulocyte migration and activation) immune pathways. The effects of UPA treatment on pBM correlating with ASDAS-CRP at baseline were consistent with UPA's broad activity on potential pathogenic pathways in both nr-axSpA and bDMARD-IR AS patients (<b>Figure 1</b>). <h3>Conclusion</h3> While presenting different degrees of axial skeletal involvement, nr-axSpA and bDMARD-IR AS patients share common pathogenic pathways, with a more pronounced dysregulation observed in the latter group as observed from our data. Treatment with UPA inhibited multiple potentially pathogenic pathways associated with disease activity at baseline in nr-axSpA and bDMARD-IR AS patients. These observations are consistent with prior analyses in bDMARD-naïve AS patients<sup>[3]</sup>. We propose that the clinical efficacy of UPA in these 2 patient populations may result, at least in part, from its broad biological activity observed at the protein level. <h3>References</h3> [1]Deodhar A, et al. <i>Lancet</i> 2022; <b>400</b>(10349): 369-79. [2]van der Heijde D, et al. <i>Ann Rheum Dis</i> 2022; <b>81</b>(11): 1515-23. [3]Sornasse T, et al. <i>Arthritis Rheumatol</i> 2020; <b>72</b>. <h3>Acknowledgements</h3> AbbVie, Inc, the study sponsor, contributed to the study design; data collection; analysis and interpretation of data; and to writing, reviewing, and approving the final version. Fang Cai, a former AbbVie employee, contributed substantially to this study by designing, planning, and organizing the data generation. <h3>Disclosure of Interests</h3> Thierry Sornasse Shareholder of: May own stock or stock options of AbbVie, Employee of: AbbVie, In-Ho Song Shareholder of: May own stock or stock options of AbbVie, Employee of: AbbVie, Peter Wung Shareholder of: May own stock or stock options of AbbVie, Employee of: AbbVie, Yingtao Bi Shareholder of: May own stock or stock options of AbbVie, Employee of: AbbVie, Buvana Ravishankar Shareholder of: May own stock or stock options of AbbVie, Employee of: AbbVie, Hengcheng Alvis Hu Shareholder of: May own stock or stock options of AbbVie, Employee of: AbbVie, Walter P Maksymowych Consultant of: AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Novartis, Pfizer, and UCB.